Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study

Finn, Richard S.; Kudo, Masatoshi; Cheng, Ann‐Lii; Wyrwicz, Lucjan; Ngan, Roger K.C.; Blanc, Jean‐Frédéric; Baron, Ari David; Vogel, Arndt; Ikeda, Masafumi; Piscaglia, Fabio; Han, Kwang Hyub; Qin, Shukui; Minoshima, Yukinori; Kanekiyo, Michio; Ren, Min; Dairiki, Ryo; Tamai, Toshiyuki; Dutcus, Corina E.; Ikezawa, Hiroki; Funahashi, Yasuhiro; Evans, T.R. Jeffry

doi:10.1158/1078-0432.ccr-20-4219

Cited by 52 publications

(52 citation statements)

References 32 publications

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“…Blood samples, collected at a pretreatment visit and within a month after administration of Lenvatinib [ 16 ], were centrifuged at 25 °C (room temperature) at 3000 rpm for 5 min. The fractionated serum was stored at − 45 °C.…”

Section: Methodsmentioning

confidence: 99%

The change rate in serum nitric oxide may affect lenvatinib therapy in hepatocellular carcinoma

et al. 2022

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Background Lenvatinib is appropriate for reducing the production of nitric oxide (NO) and facilitating as block angiogenesis. However, to our knowledge, there are no data that support the correlation between NO and clinical response in patients who received lenvatinib therapy for HCC. Therefore, we investigated the correlation between the change rate of NO levels and clinical responses including adverse events (AEs) after lenvatinib therapy for unresectable hepatocellular carcinoma (HCC). Methods This study was conducted using previously collected data from another study. We enrolled 70 patients who received lenvatinib for advanced or unresectable HCC. NO was measured by converting nitrate (NO3−) to nitrite (NO2−) with nitrate reductase, followed by quantitation of NO2− based on Griess reagent. To determine whether lenvatinib influences NO in unresectable HCC, we evaluated the influence of the change rate of NO from baseline after administration of lenvatinib on maximal therapeutic response and SAE. Results After lenvatinib administration, a change rate in the NO from 0.27 to 4.16 was observed. There was no difference between the clinical response to lenvatinib and the change rate of NO (p = 0.632). However, the change rate of NO was significantly lower in patients with AEs than in those without AEs (p = 0.030). When a reduction in NO rate of < 0.8 was defined as a clinically significant reduction of NO (CSRN), the CSRN group had significantly worse progression-free survival (PFS) and overall survival (OS) than the non-CSRN group (p = 0.029 and p = 0.005, respectively). Conclusion Decreased NO levels were associated with the occurrence of AEs and worse prognosis after lenvatinib administration. Change rate in serum NO can be used as predictive markers in patients receiving lenvatinib therapy for HCC.

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Section: Methodsmentioning

confidence: 99%

The change rate in serum nitric oxide may affect lenvatinib therapy in hepatocellular carcinoma

et al. 2022

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“… 206 Lenvatinib-treated responders showed greater increases in FGF19 and FGF23 levels than nonresponders, but higher baseline VEGF, ANG2, and FGF21 levels were correlated with shorter OS after lenvatinib or sorafenib treatment. 207 Circulating tumor cells, which escape from the tumor site, are the primary source of metastases or post-LT recurrence and have been shown to predict HCC early recurrence after LR and LT. 208 , 209 Moreover, the integration of transcriptomic and genomic data provides a global tumor picture and describes the escape mechanisms. 210 Analysis of circulating tumor DNA carrying a cancer-specific tumor framework, mutational load, immune composition, and antitumor immunity as well as immunosuppressive genetic and epigenetic aberrations enables monitoring of the effect of NAT in HCC in a noninvasive, dynamic manner.…”

Section: Selection Of Appropriate Natsmentioning

confidence: 99%

Neoadjuvant Therapy for Hepatocellular Carcinoma

Yin¹,

Chen²,

Liang³

et al. 2022

JHC

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Hepatocellular carcinoma (HCC) is characterized by low resection and high postoperative recurrence rates, and conventional treatment strategies have failed to meet clinical needs. Neoadjuvant therapy (NAT) is widely employed in the routine management of several solid tumors because it increases resectability and reduces the rate of postoperative recurrence. However, a consensus has not been reached regarding the effects of NAT on HCC. As systemic therapy, particularly targeted therapy and immunotherapy, is given for HCC treatment, accumulating evidence shows that the “spring” of NAT for HCC is imminent. In the future, HCC researchers should focus on identifying biomarkers for treatment response, explore the mechanisms of resistance, and standardize the endpoints of NAT.

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“…Otherwise, early changes in serum FGF19 and Ang-2 (an angiogenesis regulator that plays a role through TEK tyrosine kinase and endothelium receptor levels during lenvatinib treatment) might predict clinical response and PFS. In a recent study of 74 patients (BCLC stages B and C), including patients previously treated with sorafenib or regorafenib, with a median follow-up of 157 days, significantly increased FGF19 levels and decreased Ang-2 levels were seen in lenvatinib responders compared with non-responders (ratio of FGF19 level at 4 weeks/baseline in responders vs. non-responders: 2.09 vs. 1.32, respectively, p = 0.0004; ratio at 8 weeks: 2.19 vs. 1.40, p = 0.0015) [ 39 , 40 ]. In multivariate analysis, the combination of serum FGF19 and Ang-2 was the most independent predictive factor for lenvatinib response (OR: 9.143; p = 0.0012) and PFS (HR: 0.171; p = 0.0240).…”

Section: Lenvatinib In the First Line Settingmentioning

confidence: 99%

Is There Still a Place for Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma at the Time of Immunotherapies? A Focus on Lenvatinib

Decraecker

Toulouse

Blanc

2021

Cancers

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The systemic treatment of hepatocellular carcinoma is changing rapidly. Three main classes of treatment are now available. Historically, multi-targeted tyrosine kinase inhibitors (TKIs) (sorafenib and lenvatinib as first-line; regorafenib and cabozantinib as second-line) were the first to show an improvement in overall survival (OS). Anti-vascular endothelial growth factor (anti-VEGF) antibodies can be used in first-line (bevacizumab) or second-line (ramucirumab) combination therapy. More recently, immuno-oncology (IO) has profoundly changed therapeutic algorithms, and the combination of atezolizumab-bevacizumab is now the first-line standard of care. Therefore, the place of TKIs needs to be redefined. The objective of this review was to define the place of TKIs in the therapeutic algorithm at the time of IO treatment in first-line therapy, with a special focus on lenvatinib that exhibits one of the higher anti-tumoral activity among TKI in HCC. We will discuss the place of lenvatinib in first line (especially if there is a contra-indication to IO) but also after failure of atezolizumab and bevacizumab. New opportunities for lenvatinib will also be presented, including the use at an earlier stage of the disease and combination with IOs.

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Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study

Abstract: Ari Baron reports speakers' bureau fees for Amgen,

Cited by 52 publications

References 32 publications

The change rate in serum nitric oxide may affect lenvatinib therapy in hepatocellular carcinoma

The change rate in serum nitric oxide may affect lenvatinib therapy in hepatocellular carcinoma

Neoadjuvant Therapy for Hepatocellular Carcinoma

Is There Still a Place for Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma at the Time of Immunotherapies? A Focus on Lenvatinib

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